The long range goal of the proposed work is to understand the fundamental relationships between climate and vector-borne pathogen transmission. We will use more than a decade of research and data at multiple scales on the transmission ecology of West Nile virus (WNV) to determine mechanistic relationships of climate on mosquito populations and WNV transmission and the potential impacts of climate change. The proposed work addresses three specific aims: SA1) Determine the broad scale spatio-temporal correlations between rainfall and temperature and West Nile virus incidence in humans, mosquitoes, and birds, while controlling for land use. Use these patterns to generate mechanistic hypotheses about local scale processes generating these correlations. We will use more than a decade of WNV incidence in birds, mosquitoes, and humans to determine the influence of temperature and rainfall on the length of WNV transmission season, the spatial distribution of WNV, and the intensity of WNV transmission. SA2) Test mechanistic hypotheses about climate-transmission links with laboratory studies and local scale data on temperature, rainfall, host abundance and WNV seroprevalence, and mosquito abundance, feeding patterns, and WNV infection prevalence. We will perform laboratory studies to determine the influence of temperature on four critical factors in the transmission of vector-borne pathogens: vector competence, developmental rate, longevity, and biting rate of the three dominant WNV mosquito species. We will use local studies of WNV transmission at 182 sites in 6 regions spanning the east-west and north-south dimensions of the USA to determine the influence of rainfall and temperature on mosquito abundance and the intensity of WNV transmission relative to other factors. SA3) Use hypotheses supported from SA2 to predict the impacts of climate change on future WNV transmission. We will develop fine scale future climate projections and use the insights gained from aims 1&2 to predict the effects of climate change on the distribution of WNV in North America, the length of the WNV transmission season, and the intensity of transmission across the USA. PUBLIC HEALTH RELEVANCE: Climate change presents important risks for human health, including, vector-borne, water-borne, and food-borne disease, heat stress, air pollution, extreme weather events. The impact of climate on vector-borne disease is one of the more difficult issues to address, because increasing temperature and changes in rainfall can have both positive and negative impacts on pathogen transmission, making simple directional predictions tenuous. As a result, determining the impact of climate change on vector-borne disease requires a multi-scale approach where the mechanisms of climate impacts on local scale transmission can determined, followed by a scaling up of these mechanisms to a scale that is relevant for public health. Current and previous work on West Nile virus presents an opportunity to attack the problem head-on with this multi- scale approach, which will facilitate public health intervention for this, and other vector-borne diseases.